Semi-synthesis, biological evaluation and molecular docking studies of novel Benzylidene-2,4-thiazolidinedione derivatives from natural maslinic acid

• An efficient procedure for the isolation of Maslinic acid (MA) from olive pomace. • Semi-synthesis of new benzylidene-2,4-Thiazolidinedione derivatives from MA. • Evaluation of the anti-15-lipoxygenase, antidiabetic and cytotoxic activities. • Molecular docking studies were carried. • The new hybrid molecules show promise as potential therapeutic agent candidates. In the present study, maslinic acid (MA) was effectively isolated from olive pomace ( Olea europaea L.) using an ultrasonic bath affording (2.93 mg/g DW), through a highly efficient methodology. A series of eleven novel benzylidene 2,4-thiazolidinedione derivatives were synthesized from MA via a Knoevenagel reaction using various arylaldehydes. 1 H NMR, 13 C NMR and HRMS-ESI analysis were used to characterize the structures of all newly synthesized compounds. Thereafter, in vitro biological assays were conducted to assess their inhibitory activities on 15-lipoxygenase (15-LOX), α -glucosidase, α -amylase enzymes as well as the cytotoxic activity against HCT 116 (Human colon carcinoma) and LS174T (Human colon adenocarcinoma) cancer cell lines. Within this series, it has been found that the highest activity against α -amylase (IC 50 = 39.7 μM) was obtained for analog 4k . On the other hand, compound 4i stands to be the most potent inhibitor of α -glucosidase enzyme with an IC 50 value of 51.3 μM. It is worth noting that derivatives 2 and 4e , both bearing a para -propylphenyl substituent on the arylidene moiety, exhibited significantly enhanced inhibitory activity against the 15-LOX enzyme (IC 50 = 50.9 and 34.8 μM, respectively), surpassing that of the parent compound 1 . The derivative 3 was the most cytotoxic agent against both cancer cell lines LS174T (IC 50 = 30.4 μM) and HCT 116 (IC 50 = 71.6 μM). Consequently, the most active compounds were subjected to molecular docking studies against targets involved in the enzymatic assays including 15-LOX, α -glucosidase and α -amylase. The docking results revealed key hydrogen bonding interactions, along with other interactions, that supported the observed biological activities and informed the structure-activity relationship (SAR) analysis.